Several studies have now examined the cDNA expression profiles of healthy myometrium, leiomyomas (LM), and leiomyosarcomas (LMS). This has produced a list of candidate genes that might be useful tools for distinguishing these entities from each other. The potential candidates identified from this body of research include insulinlike growth factor 1, h-caldesmon, cytokeratin 18, and the cyclin-dependent kinase 4 inhibitor, p16. To determine whether the immunohistochemical expression of these proteins could aid in the diagnosis of LMS and LM variants, we constructed a tissue microarray consisting of cases of healthy myometrium (n = 10), LM (not otherwise specified and variants; n = 47), and LMS (n = 8), and then measured the immunoreactivity of each of these proteins. The cases were scored on the basis of staining intensity (weak, moderate, or strong) and extent (focal or diffuse) and were assigned a final score from 0 to +3. Immunostaining for p16 was statistically stronger in LMS than in LM and its subtypes (P < 0.001). Specifically, the p16 immunostaining score in LMS cases (n = 8) was at least +2, whereas the p16 immunostaining scores in all LM cases (n = 47) were either 0 (n = 35) or +1 (n = 12). The expression of the remaining antibodies did not show a statistically significant difference between the 2 groups. Furthermore, none of the markers studied showed any differences among the LM variants. The results of this study confirm the overexpression of p16 in LMS and suggest that p16 can serve as a reliable immunohistochemical marker in distinguishing uterine LMS from LM and its benign variants.

Paclitaxel (Taxol) kills tumor cells by inducing both cellular necrosis and apoptosis. A major impediment to paclitaxel cytotoxicity is the establishment of multidrug resistance whereby exposure to one chemotherapeutic agent results in cross-resistance to a wide variety of other drugs. For example, selection of MCF-7 breast cancer cells for resistance to doxorubicin (MCF-7ADR cells) results in cross-resistance to paclitaxel. This appears to involve the overexpression of the drug transporter P-glycoprotein which can efflux both drugs from tumor cells. However, MCF-7ADR cells possess a deletion mutation in p53 and have considerably reduced levels of the Fas receptor, Fas ligand, caspase-2, caspase-6, and caspase-8, suggesting that paclitaxel resistance may also stem from a bona fide block in paclitaxel-induced apoptosis in these cells. To address this issue, we examined the ability of the P-glycoprotein inhibitor valspodar to restore paclitaxel accumulation, paclitaxel cytotoxicity, and paclitaxel-induced apoptosis. Compared to drug sensitive MCF-7 cells, MCF-7ADR cells accumulated >6-fold less paclitaxel, were approximately 100-fold more resistant to killing by the drug, and were highly resistant to paclitaxel-induced apoptosis. In contrast, MCF-7ADR cells pretreated with valspodar were indistinguishable from drug-sensitive cells in their ability to accumulate paclitaxel, in their chemosensitivity to the drug, and in their ability to undergo paclitaxel-induced apoptosis. Valspodar, by itself, did not affect these parameters. This suggests that the enhancement of paclitaxel toxicity in MCF-7ADR cells involves a restoration of apoptosis and not solely through enhanced drug-induced necrosis. Morever, it appears that changes in the levels/activity of p53, the Fas receptor, Fas ligand, caspase-2, caspase-6, or caspase-8 activity have little effect on paclitaxel-induced cytotoxicity and apoptosis in human breast cancer cells.

We describe a 49-year-old man who presented to hospital with unstable angina and who underwent emergency coronary artery bypass grafting. During the surgical procedure, an incidental anterior mediastinal mass was discovered. Histological examination of this mediastinal mass revealed a thymolipoma containing numerous polygonal, striated myoid cells that were immunoreactive for desmin, muscle-specific actin and myoglobin. Electron microscopy demonstrated numerous Z band structures confirming myoid differentiation. Even though the appearance of myoid cells in thymolipoma may be alarming, this tumor should be recognized as a benign entity. Thymolipomas containing striated myoid cells should be differentiated from more ominous thymic neoplasms, including teratomas and thymic liposarcomas. To our knowledge, this is only the third reported case of thymolipoma containing striated myoid cells.

The drug transporter P‐glycoprotein (P‐gp) appears to play an important role in the ability of tumor cells to evade killing by chemotherapeutic agents. Using pharmacological inhibitors of cAMP‐dependent protein kinase (PKA), it has been suggested that, similar to rodent model systems, the human P‐gp gene (MDR1) is also under PKA‐dependent control and that PKA inhibition may prove useful in reducing drug resistance in human cancer cells. To test this hypothesis, we stably transformed doxorubicin (Adriamycin)‐resistant human MCF‐7 breast cancer cells (MCF‐7ADR) with a vector that inhibits PKA activity by inducing over‐expression of mutant type Iα PKA regulatory (RIα) subunits. Two transformants (MCF‐7ADR‐A and MCF‐7ADR‐B) were found to express mutant RIα subunits and to possess markedly reduced PKA activity; another transformant (MCF‐7ADR‐9) lacked mutant RIα subunit expression and exhibited no inhibition of PKA activity. In contrast with findings in Chinese hamster ovary and Y1 adrenal cells, P‐gp levels and cellular sensitivity to drugs which are P‐gp substrates were unchanged in the PKA‐inhibited transformants, suggesting that P‐gp expression and function are not under PKA‐dependent control in MCF‐7ADR cells. Growth and saturation densities of the cell lines were highly correlated with level of PKA catalytic activity, suggesting that PKA inhibition may prove useful in inhibiting growth of breast tumor cells, even upon establishment of resistance to doxorubicin. However, our results challenge current proposals that drug sensitivity in P‐gp‐expressing human tumor cells may be restored by blocking MDR1 gene expression through inhibition of PKA activity. Int. J. Cancer 82:893–900, 1999. © 1999 Wiley‐Liss, Inc.

Fungal endocarditis is an uncommon complication of pacemaker implantation and is associated with high mortality rates (1). Survival is largely dependent on early diagnosis and treatment. However, late diagnosis is common due to the frequency of nonspecific clinical symptoms, negative blood cultures and delays in obtaining appropriate imaging studies. A high index of suspicion for fungal endocarditis should be maintained in individuals with implantable pacemakers and fever of an uncertain source, especially in the context of negative blood cultures. We report a patient with rare pacemaker lead endocarditis due to Aspergillus fumigatus, and review the diagnostic and treatment considerations. CASE PRESENTATIONA 71-year-old man was admitted with a two-week history of chest pain and a one-week history of low-grade fever (less than 39°C). His medical history was significant for myocardial infarction, atrial fibrillation and asystolic arrest, leading to pacemaker insertion 23 years previously. Numerous pacemakerrelated complications had led to five pacemaker revisions. Superior vena cava (SVC) syndrome, secondary to pacemaker lead fibrosis, was treated on two separate occasions with percutaneous catheter dilation and stenting, most recently performed four months before presentation. He was receiving chronic anticoagulation with warfarin, and antiplatelet therapy consisting of acetylsalicylic acid and clopidogrel. He had no history of being immunocompromised.Physical examination revealed a temperature of 38.5°C. Chronic plethora due to longstanding SVC obstruction was observed. There were no cardiac murmurs or extra heart sounds. No stigmata of infectious endocarditis were observed. The remainder of the physical examination was unremarkable. Pertinent laboratory data included a hemoglobin count of 113 g/L, white blood cell count of 3.8×10 9 /L, platelet count of 153×10 9 /L, erythrocyte sedimentation rate of 102 mm/h, C-reactive protein concentration of 163 mg/L and international normalized ratio of 2.8. There was no biochemical or electrocardiographic evidence of myocardial infarction. Multiple blood cultures performed during the patient's sixweek admission were negative and no antimicrobial therapy was initiated. The diagnosis of fungal endocarditis requires a high index of clinical suspicion. Rarely, pacemaker implantation may be a risk factor for the development of fungal endocarditis. A 71-year-old man with a history of multiple transvenous pacemaker manipulations and fever of an uncertain source is described. A diagnosis of culture-negative pacemaker endocarditis was established only after repeat transthoracic echocardiography. Amphotericin B was instituted; however, the patient developed a cerebral infarct and died. Postmortem examination demonstrated Aspergillus fumigatus within a large pacemaker lead thrombus, tricuspid and aortic valve vegetations, and septic pulmonary and renal emboli. The present report describes the clinical and pathological features of a rare case of Aspergillus fumigatus pacemaker lead en...